Electron transit through a urethane linkage has been utilized to construct prodrugs by Senter, P. D. et al., J Org Chem (1990), 55:2975. In this work, the reduction of a disulfide bridging two phenyl moieties was used to mediate the release of either nitroaniline or mitomycin C, wherein the amino group of the substance released was part of a urethane linkage para to the disulfide on one of the phenyl moieties. The reduction released electrons through the phenyl moiety to decompose the urethane. This provided the released nitroaniline or mitomycin C, and CO.sub.2 as a by-product.
In addition, Nicolaou, K. C. et al., Angew Chem Int Ed Engl (1991) 30:1032 describe the release of a dynemycin A analog wherein the amino group of the dynemycin A analog was included as part of a urethane linkage to the moiety .phi.--SO.sub.2 CH.sub.2 OC(O)--N. Neither of these prodrug type molecules is enzyme regulated.
PCT/US1994/11109 referenced and incorporated above was published Apr. 13, 1995 as WO95/09866. This published application describes a set of glutathione S-transferase activated compounds wherein the release of a desired leaving group is actuated by abstraction of a hydrogen ion .alpha. to the cysteinyl sulfur atom in a glutathione analog. The nature of the glutathione analog will determine which isoenzyme of GST will be the most effective in activating the release of the leaving group. Also disclosed in WO95/09866 is the inclusion of a urethane linkage within the leaving group, so that CO.sub.2 is released when the leaving group is released as well.
The use of a conjugated .pi. system to participate in the transfer of electrons from a relevant portion of a prodrug to the group released is also described by Papanastassiou, Z. B. et al., Experientia (1968) 24:325 and Tercel, M. et al., J Med Chem (1993) 36:2578, as well as in the PCT reference described above.
It has now been found that the enzyme specificity conferred by the nature of glutathione analogs can be coupled with the electron release mechanisms associated with the urethane linkage to provide a new class of effective prodrugs for a variety of nitrogen-containing pharmaceuticals as well as more generally a release mechanism for any moiety containing reduced nitrogen. In addition, by taking advantage of the ability to move electrons through a conjugated system, the urethane-mediated linkage can be employed to release moieties which do not contain reduced nitrogen as part of the urethane linkage per se.